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Cerebral aspergillosis is increasingly recognized in severely immunocompromised patients and, until recently, this type of fungal infection was associated with a mortality approaching 100%. The central nervous system is a protected environment and penetration of drugs across the blood-brain barrier is mainly limited by their molecular size and physicochemical properties, as well as drug interaction with transporter systems (e.g., P-glycoprotein) at the blood-brain barrier. Most antifungal agents are large molecules (>700 Da), which makes sufficient penetration into the central nervous system unlikely. In fact, the available data indicate low levels of most antifungal agents in cerebrospinal fluid and brain tissue, except for fluconazole and voriconazole. Concentrations of voriconazole exceeding inhibitory concentrations for Aspergillus species were found repeatedly in cerebrospinal fluid and brain tissue, including brain abscess material. A recent retrospective study confirmed that voriconazole treatment resulted in improved response and survival rates in patients with cerebral aspergillosis. Data from animal models, which explored escalated doses or combinations of antifungal agents in experimental neuroaspergillosis, suggest that selected combination or dose-escalated therapies might further improve the still unsatisfactory prognosis in this particular type of Aspergillus infection.

For an adolescent with bacterial meningitis and subsequent cerebral aspergillosis, intravenous voriconazole dose requirements substantially decreased during coadministration with intravenous chloramphenicol and considerably rose after discontinuation of the antibiotic. In agreement with in vitro evidence, these data suggest that chloramphenicol is a rather significant inhibitor of hepatic CYP3A4 and/or CYP2C19.

Invasive aspergillosis is an increasing problem in immuno-incompetent patients after prolonged steroid therapy, cancer radio-chemotherapy, and bone marrow or solid organ transplantation. Cerebral aspergillosis is a well-described complication of the invasive aspergillosis but only in rare cases, the brain is the sole site of infection. Despite increasing availability of antifungal drugs, the prognosis of cerebral aspergillosis is poor. We report on an 11-year-old boy with medulloblastoma in the area of the fourth ventricle. Following tumor surgery and radio-chemotherapy, several abscess-like structures occurred in the operating field. After incomplete abscess, resection histology and culture confirmed a localized Aspergillus fumigatus infection. The initial treatment of the Aspergillus fumigatus infection with conventional amphotericin B failed, and treatment with the triazole voriconazole was started. Intravenous treatment with voriconazole resulted in a reduction of the Aspergillus fumigatus abscess. After switching to oral ambulatory therapy, the Aspergillus fumigatus abscess increased in size. To improve treatment, voriconazole dosage was adapted to reach drug concentrations in cerebrospinal fluid (CSF) above the minimal fungicidal concentration and plasma specimens. During the concentration-controlled voriconazole therapy for a period of 18 months, a complete response was achieved.